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WO2018088439A1 - Procédé de modification d'une population de lymphocytes t - Google Patents

Procédé de modification d'une population de lymphocytes t Download PDF

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Publication number
WO2018088439A1
WO2018088439A1 PCT/JP2017/040302 JP2017040302W WO2018088439A1 WO 2018088439 A1 WO2018088439 A1 WO 2018088439A1 JP 2017040302 W JP2017040302 W JP 2017040302W WO 2018088439 A1 WO2018088439 A1 WO 2018088439A1
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Prior art keywords
group
compound
rdhi
oxo
heptamethyl
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Ceased
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PCT/JP2017/040302
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English (en)
Japanese (ja)
Inventor
治夫 杉山
文博 藤木
正博 閨
晋哉 河野
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KNC Laboratories Co Ltd
University of Osaka NUC
Original Assignee
Osaka University NUC
KNC Laboratories Co Ltd
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Publication date
Application filed by Osaka University NUC, KNC Laboratories Co Ltd filed Critical Osaka University NUC
Priority to DK17870242.9T priority Critical patent/DK3539974T5/da
Priority to EP17870242.9A priority patent/EP3539974B1/fr
Priority to JP2018550232A priority patent/JP6994201B2/ja
Priority to US16/347,337 priority patent/US10899790B2/en
Priority to ES17870242T priority patent/ES2946188T3/es
Publication of WO2018088439A1 publication Critical patent/WO2018088439A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • C07J—STEROIDS
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
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    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
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    • C12N2501/30—Hormones
    • C12N2501/38—Hormones with nuclear receptors
    • C12N2501/39—Steroid hormones

Definitions

  • the present invention relates to a method for regulating the differentiation of immune cells, particularly T cells, and modifying the T cell population. Specifically, the present invention relates to compounds that increase the proportion of memory T cells in a population of T cells, methods for increasing the proportion of memory T cells in a population of T cells using the same, and the like.
  • Immunotherapy generally refers to a method of treating a disease by activating a patient's immune system by various methods or introducing immune cells activated outside the patient's body into the patient's body.
  • various methods such as immune cell therapy, peptide vaccine therapy, cytokine therapy, and antibody therapy have been developed so far.
  • Patent Documents 1 to 4 and Non-Patent Document 1 In recent years, by stimulating immune cells (particularly antigen-presenting cells and T cells) with a partial peptide derived from the oncogene product WT1 (WT1 peptide), induction of tumor-specific cytotoxic T cells (CTL) and helper T It has been found that cell activation can be achieved (Patent Documents 1 to 4 and Non-Patent Document 1), and research toward practical use as a cancer immunotherapy with a WT1 peptide vaccine is underway.
  • WT1 peptide oncogene product WT1
  • CTL tumor-specific cytotoxic T cells
  • helper T It has been found that cell activation can be achieved (Patent Documents 1 to 4 and Non-Patent Document 1), and research toward practical use as a cancer immunotherapy with a WT1 peptide vaccine is underway.
  • immunotherapy may not be sufficiently effective, and development of a method for enhancing the effect of immunotherapy is desired.
  • the present inventors have found that by regulating the retinoid metabolic pathway or the retinoic acid signaling system, the proportion of memory T cells in the T cell population can be increased and the immune response in the subject can be enhanced (Patent Literature). 5).
  • An object of the present invention is to search for compounds that can increase the proportion of memory T cells in a T cell population by regulating a retinoid metabolic pathway or a retinoic acid signal transduction system and enhance an immune response in a subject.
  • the present inventors searched for compounds that can increase the proportion of memory T cells in the T cell population by modulating the retinoid metabolic pathway or retinoic acid signaling system and enhance the immune response in the subject.
  • the compound of I) or a pharmaceutically acceptable salt or hydrate thereof can increase the proportion of memory T cells in the T cell population and enhance the immune response in the subject by inhibiting the retinoid metabolic pathway.
  • the present invention has been completed.
  • the present invention provides the following: (1) Formula (I): [Wherein A is a 5- or 6-membered ring, ------ is a single bond or double bond, m is an integer from 0 to 2, n is an integer from 0 to 2, R 1 may be substituted with a C 1-6 alkyl group —NH 2 , —OH, ⁇ O, ⁇ NOH, —NHC (O) —R 13 , —NHC (O) NH—R 14 , or — OC (O) -R 15 , R 2 is —C 1-6 alkyl group, optionally substituted with C 1-6 alkyl group —C 1-6 alkenyl group, optionally substituted with C 1-6 alkyl group —C (O) OH, C 1-6 alkyl group optionally substituted with -NHC (O) OH or C 1-6 alkyl optionally -C be substituted with a group (O) NH 2,
  • R 3 is —H, ⁇ O,
  • An agent for increasing the proportion of memory T cells comprising the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof.
  • a preventive and / or therapeutic agent for cancer or infectious disease comprising the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof.
  • An adjuvant for cancer immunotherapy comprising the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof.
  • An immunopotentiator comprising the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof.
  • a T cell having an increased proportion of memory T cells comprising adding the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof to the T cell population.
  • the present invention provides the following. (11) Use of the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of an inhibitor of a retinoid metabolic pathway. (12) Use of the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of an agent for increasing the proportion of memory T cells. (13) Use of the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of a preventive and / or therapeutic agent for cancer or infectious disease. (14) Use of the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof in the production of an adjuvant for immunotherapy of cancer.
  • the present invention provides the following. (16) Use of the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof for inhibiting a retinoid metabolic pathway. (17) Use of the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof for increasing the proportion of memory T cells. (18) Use of the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof for the prevention and / or treatment of cancer or infectious diseases. (19) Use of the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof for assisting immunotherapy of cancer.
  • the present invention provides the following.
  • (21) A method for inhibiting a retinoid metabolic pathway in a subject in need of inhibiting the retinoid metabolic pathway, the compound according to any one of (1) to (4), or a pharmaceutically acceptable salt or water thereof Administering a Japanese to the subject.
  • (22) A method for increasing the proportion of memory T cells in a subject in need of increasing the proportion of memory T cells, the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt thereof Administering a salt or hydrate to the subject.
  • a method for preventing and / or treating cancer or an infectious disease in a subject in need of prevention and / or treatment of cancer or an infectious disease comprising the compound according to any one of (1) to (4) or a method thereof Administering a pharmaceutically acceptable salt or hydrate to the subject.
  • a method of assisting cancer immunotherapy in a subject in need of cancer immunotherapy comprising the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or water thereof Administering a Japanese to the subject.
  • the present invention provides the following.
  • a kit for inhibiting a retinoid metabolic pathway comprising the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof.
  • a kit for increasing the proportion of memory T cells comprising the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof.
  • a kit for preventing and / or treating cancer or an infectious disease comprising the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof .
  • a kit for immunotherapy of cancer comprising the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof.
  • a kit for enhancing immunity comprising the compound according to any one of (1) to (4) or a pharmaceutically acceptable salt or hydrate thereof.
  • a compound found in the present invention or a pharmaceutically acceptable salt or hydrate thereof can enhance an immune response to an antigen in a subject through an increase in the proportion of memory T cells in the T cell population. Therefore, the method for increasing the proportion of memory T cells of the present invention, the preventive / therapeutic agent for cancer / infection, the cancer immunotherapy adjuvant, the immunity enhancing agent, the T cell population preparation method, the T cell population prepared by the method, etc. It can be used for prevention / treatment of various diseases including cancer and infectious diseases. Moreover, the effect of this immunotherapy can be heightened by combining these with immunotherapy for various diseases including cancer and infectious diseases.
  • FIG. 1 is a graph showing the inhibitory effect of RDH10 enzyme activity by the compounds of the present invention.
  • the compound is indicated by the applicant's serial number (RDHI-No.).
  • FIG. 2 is a graph showing the amplification of memory T cells and the reduction of effector T cells by the compound of the present invention.
  • the compound is indicated by the applicant's serial number (RDHI-No.).
  • FIG. 3 is a scheme showing the experimental procedure for examining the in vivo effects of the compounds of the present invention.
  • FIG. 4 is a graph showing the in vivo tumor growth inhibitory effect of the compound of the present invention over time. The compound is indicated by the applicant's serial number (RDHI-No.).
  • FIG. 1 is a graph showing the inhibitory effect of RDH10 enzyme activity by the compounds of the present invention.
  • the compound is indicated by the applicant's serial number (RDHI-No.).
  • FIG. 2 is a graph showing the amplification of memory T cells and the reduction of effector T cells by the
  • FIG. 5 shows the results of flow cytometry showing the amplification of CD45.1 + OT-1 cells (OVA-specific CD8 + cells) in vivo by the compounds of the present invention.
  • the compound is indicated by the applicant's serial number (RDHI-No.).
  • FIG. 6 is a graph showing the results of analyzing the expression intensity of CD62L and CD127 in the OT-I cells shown in FIG. 5 by flow cytometry.
  • the compound is indicated by the applicant's serial number (RDHI-No.).
  • T cells differentiate from undifferentiated naive T cells into subsets of T cells with various functions.
  • those that play a major role in the immune response are CD4 positive T cells (helper T cells) and CD8 positive T cells (killer T cells).
  • Both CD4 positive T cells and CD8 positive T cells can be classified into memory cells (central memory cells and effector memory cells) and effector cells (effector cells and terminal effector cells) according to the stage of differentiation.
  • positive CD antigen expression is represented by “ + ” and negative is represented by “ ⁇ ”.
  • CD4 positive T cells are represented as CD4 + T cells.
  • T cell subsets can be determined by identifying surface antigens expressed by cells, cytokines produced, interferons, and the like.
  • CD4 + T cells and CD8 + T cells are expressed by central memory cells (CD127 + , CD62L + ), effector memory cells (CD127 + , CD62L ⁇ ), effector cells (CD127 ⁇ , and CD62L + ) by the expression of the surface antigens CD127 and CD62L.
  • CD62L + ) or terminal effector cells CD127 ⁇ , CD62L ⁇ ).
  • Stimulated T cells differentiate in the order of central memory cells, effector memory cells, effector cells, and terminal effector cells. Of these cells, central memory cells have the highest proliferation ability and the highest IL-2 production.
  • the characteristics of the memory T cell include that it is difficult to cause apoptosis and has a strong proliferation ability. Thus, increasing the proportion of memory T cells in the T cell population by the method of the present invention contributes to achieving stronger immunity.
  • the increase in the proportion of memory T cells is performed using a compound that inhibits the retinoid metabolic pathway.
  • the proportion of memory T cells, particularly central memory T cells, in the T cell population is increased.
  • inhibition of the retinoid metabolic pathway means any reaction in the metabolic pathway in which retinoic acid is produced from vitamin A (retinoid) or provitamin A (retinoid precursor) such as retinol and ⁇ -carotene. It refers to inhibiting.
  • the inhibitor of the retinoid metabolic pathway is a reaction that converts retinol to retinal, a reaction that converts retinal to retinoic acid, a reaction that converts ⁇ -carotene to retinal, ⁇ -apocarotenal to ⁇ -carotene One or more of the reaction to convert to ⁇ -apocarotenal and the reaction to convert ⁇ -apocarotenal to retinal and retinoic acid.
  • Inhibitors of the retinoid metabolic pathway are enzymes that catalyze any reaction in the retinoid metabolic pathway (hereinafter also referred to as “retinoid metabolic enzymes”), such as retinol dehydrogenase, retinal oxidase, retinal dehydrogenase, ⁇ -carotene-15, It inhibits the expression or action of 15′-monooxygenase 1 (BCMO1), ⁇ -carotene oxygenase 2 (BCO2) and the like.
  • retinoid metabolic enzymes such as retinol dehydrogenase, retinal oxidase, retinal dehydrogenase, ⁇ -carotene-15, It inhibits the expression or action of 15′-monooxygenase 1 (BCMO1), ⁇ -carotene oxygenase 2 (BCO2) and the like.
  • BCMO1 15′-monooxygenase 1
  • BCO2 ⁇ -carotene oxygena
  • the inhibitor of retinoid metabolic pathway is an inhibitor of retinol dehydrogenase, more preferably retinol dehydrogenase 10 consisting of the amino acid sequence of SEQ ID NO: 1 (the sequence of DNA encoding the enzyme is shown as SEQ ID NO: 2). ) Or its homologue inhibitors.
  • the homologue of retinol dehydrogenase 10 is an amino acid sequence having sequence identity of 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more with the amino acid sequence of SEQ ID NO: 1. 1 or several, for example 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acids are substituted in the amino acid sequence of SEQ ID NO: 1, A protein consisting of an amino acid sequence deleted, inserted and / or added.
  • the retinoid metabolic pathway inhibitor is a compound represented by the following formula (I) and pharmaceutically acceptable salts and solvates thereof.
  • An antibody or an antigen-binding fragment thereof for example, Fab, F (ab ′) 2 etc.
  • ScFv which binds a compound represented by the formula (I) and pharmaceutically acceptable salts and solvates thereof to a retinoid metabolic enzyme, etc.
  • it may be used in combination with a molecule that suppresses the expression of a gene encoding a retinoid-metabolizing enzyme (for example, siRNA, shRNA, miRNA, stRNA, and antisense RNA), or a retinoic acid signal transduction system inhibitor.
  • the proportion of memory T cells is increased by adding a compound that inhibits the retinoid metabolic pathway to the T cell population.
  • a compound that inhibits the retinoid metabolic pathway may be performed in vitro or may be performed in vivo.
  • An example of in vitro addition is the addition of the regulator to the medium in which the T cell population is cultured.
  • An example of in vivo addition is injecting the modulator into a subject's body.
  • the inhibitor of retinoid metabolic pathway in the present invention is a compound that inhibits the action of retinol dehydrogenase, preferably a compound that inhibits the action of retinol dehydrogenase 10 (SEQ ID NO: 1) (hereinafter also referred to as “RDH10 inhibitor”). is there.
  • the RDH10 inhibitor is a compound that inhibits the action of a compound retinol dehydrogenase having the structure represented by the following formula (I), and preferably inhibits the action of retinol dehydrogenase 10 (SEQ ID NO: 1).
  • Compound hereinafter also referred to as “RDH10 inhibitor”.
  • the RDH10 inhibitor may be a compound having a structure represented by the following formula (I) or a salt thereof.
  • the present invention in one aspect provides a compound of formula (I) [Wherein, A is a 5- or 6-membered ring, ------ is a single bond or double bond, m is an integer of 0 to 2, n is an integer of 0 to 2, and R 1 is C 1- —NH 2 , —OH, ⁇ O, ⁇ NOH, —NHC (O) —R 13 , —NHC (O) NH—R 14 , or —OC (O) —R optionally substituted with 6 alkyl groups 15, R 2 is -C 1-6 alkyl group, C 1-6 alkyl optionally substituted -C 2-6 alkenyl group with a group, optionally substituted by C 1-6 alkyl group -C ( O) OH, C 1-6 alkyl optionally substituted with a group -NHC (O) OH or C 1-6 -C optionally substituted with an alkyl group (O) NH 2, R 3 , is - H,
  • ring A is a 6-membered ring, ------ is a single bond or double bond, m is 2, n is 2, and R 1 is substituted with a methyl group.
  • the compound of the formula (I) includes all types of isomers regardless of structural isomers and stereoisomers.
  • the compounds of formula (I) and their pharmaceutically acceptable salts and solvates can increase the proportion of memory T cells in a T cell population by inhibiting the retinoid metabolic pathway.
  • the compound represented by the formula (I) can be synthesized by a known method.
  • the compound of the present invention can be synthesized by a known method using 18 ⁇ - or 18 ⁇ -glycyrrhetinic acid as a starting material.
  • the salts of the compounds of the present invention are also included in the present invention.
  • the said salt can be manufactured in accordance with a conventional method using the compound shown by the formula (I) provided by this invention.
  • the compound of the above formula (I) has a basic group such as an amino group or a pyridyl group
  • the compound is converted to an acid addition salt by treating with an acid. Can do.
  • Examples of the acid addition salt of the compound of the present invention include hydrohalates such as hydrochloride, hydrofluoride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates and carbonates; lower alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; arylsulfones such as benzenesulfonate and p-toluenesulfonate Acid salts; organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate; and acid addition salts that are organic acids such as amino acids such as glutamate and aspartate Although not limited to these, it is not limited to these.
  • the compound of the present invention when it has an acidic group such as a carboxyl group, it can be converted into a base addition salt by treating the compound with a base.
  • base addition salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, salts with organic bases such as ammonium salts, guanidine, triethylamine, and dicyclohexylamine. It is not limited to these.
  • the compound of the present invention may exist as an arbitrary solvate of the free compound or a salt thereof.
  • solvates of the compounds of the present invention include, but are not limited to, hydrates.
  • compound of the present invention includes compounds of the formula (I), and salts and solvates thereof, unless otherwise specified.
  • the compounds of the present invention may exist as possible isomers.
  • they may exist as geometric (cis or trans) isomers, optical isomers (enantiomers, antipodes), racemates, or mixtures thereof.
  • the possible isomers or mixtures thereof are within the scope of the present invention.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, for example, Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isoamyl group, neopentyl group, isopentyl group, 1,1-dimethylpropyl group, 1- Methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1, 2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2,3-dimethylbut
  • Specific examples of preferred compounds represented by formula (I) of the present invention include, but are not limited to, the compounds shown in Table 1 and pharmaceutically acceptable salts and solvates thereof.
  • Table 2 shows the IUPAC names of the compounds in Table 1.
  • RDH10 enzyme activity inhibitors include Compound No. 1 (RDHI012): (2S, 4aS, 6aS, 6bR, 8aR, 12aS, 12bR, 14bS) -methyl 10-amino-2,4a, 6a, 6b, 9,9,12a-heptamethyl-13-oxo- 1,2,3,4,4a, 5,6,6a, 6b, 7,8,8a, 9,10,11,12,12a, 12b, 13,14b-icosahydropicene-2-carboxylate, Compound No.
  • RDH10 enzyme activity inhibitors include Compound No.-1 (RDHI-012): (2S, 4aS, 6aS, 6bR, 8aR, 12aS, 12bR, 14bS) -methyl 10-amino-2,4a, 6a, 6b, 9,9,12a-heptamethyl-13 -Oxo-1,2,3,4,4a, 5,6,6a, 6b, 7,8,8a, 9,10,11,12,12a, 12b, 13,14b-icosahydropicene-2- Carboxylate, Compound No.
  • RDH10 enzyme activity inhibitor Compound No. 1 (RDHI-012): (2S, 4aS, 6aS, 6bR, 8aR, 12aS, 12bR, 14bS) -methyl 10-amino-2,4a, 6a, 6b, 9,9,12a-heptamethyl-13- Oxo-1,2,3,4,4a, 5,6,6a, 6b, 7,8,8a, 9,10,11,12,12a, 12b, 13,14b-icosahydropicene-2-carboxy Lat, Compound No.
  • the preventive and / or therapeutic agent for cancer and / or infectious disease of the present invention comprises an inhibitor of a retinoid metabolic pathway as an active ingredient. Inhibition of the retinoid metabolic pathway increases the proportion of memory T cells in the T cell population.
  • the preventive and / or therapeutic agent for cancer and / or infectious disease of the present invention increases the therapeutic effect of cancer by immunotherapy, particularly immunotherapy using a cancer antigen peptide.
  • cancer antigen peptides used for cancer immunotherapy include, but are not limited to, various WT1 peptides such as human WT1 332 (SEQ ID NO: 3, described in International Publication No. 2012/046730), MAGE-A4 278-299 ( SEQ ID NO: 4), survivin 97-111 (SEQ ID NO: 5), and mutant peptides having activity equivalent to them.
  • regulators of retinoid metabolic pathways or retinoic acid signaling systems are also effective as adjuvants in the prevention (eg, vaccines) and treatment (eg, immunotherapy) of infectious diseases.
  • the cancer to which the preventive / therapeutic agent for cancer / infection of the present invention is applied is not particularly limited, and includes carcinoma, sarcoma, hematopoietic tumor and the like.
  • the agent is applied to various cancers or tumors that express the WT1 gene, for example, hematopoietic tumors such as leukemia, myelodysplastic syndrome, multiple myeloma, malignant lymphoma, as well as gastric cancer, Solid cancers or solid tumors such as cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer, and brain tumor.
  • hematopoietic tumors such as leukemia, myelodysplastic syndrome, multiple myeloma, malignant lymphoma
  • Solid cancers or solid tumors such as cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer
  • the infectious disease to which the preventive / therapeutic agent for cancer / infectious disease of the present invention is applied is not particularly limited. This is because inhibitors of the retinoid metabolic pathway provide strong immunity regardless of the type of infection through an increase in the number of T cells and an increase in the proportion of memory T cells.
  • the application target of the agent may be an infection caused by bacteria, viruses, protozoa, and the like.
  • an inhibitor of a retinoid metabolic pathway can be used as an active ingredient of an immunity enhancing agent that non-specifically improves the immunity of a subject.
  • Agents such as the preventive and / or therapeutic agents for cancer and / or infectious diseases of the present invention described above, cancer immunotherapy adjuvants and immunity enhancing agents, other than the retinoid metabolic pathway inhibitors that are active ingredients, for example, , Carriers, excipients and the like.
  • the method of administering the preventive and / or therapeutic agent for cancer and / or infectious disease, the adjuvant for cancer immunotherapy, and the immunity enhancing agent of the present invention is appropriately selected according to conditions such as the type of disease, the condition of the subject, and the target site. can do. Examples of the method include, but are not limited to, intradermal administration, subcutaneous administration, intramuscular administration, intravenous administration, nasal administration, and oral administration.
  • Method for preparing T cell population In the method for preparing T cell population of the present invention, by adding an inhibitor of retinoid metabolic pathway to T cell population, the ratio of memory T cells can be increased as compared with a commonly used T cell culture method. An expanded T cell population is obtained.
  • the inhibitor of the retinoid metabolic pathway can be added to the T cell population in vitro or in vivo, but preferably in vitro.
  • An example of in vitro addition is the addition of a retinoid metabolic pathway inhibitor to the medium in which the T cell population is cultured.
  • An example of in vivo addition is the administration of a retinoid metabolic pathway inhibitor into the subject's body.
  • the T cell population produced by the T cell population production method of the present invention is used for the prevention and / or treatment of various diseases, preferably cancer or infectious diseases, particularly in the immunotherapy of cancer or infectious diseases. Can be used to increase the effect of.
  • the cancer and / or infectious disease prevention and / or treatment methods and cancer and / or infectious disease prevention and treatment kits of the present invention include an inhibitor of a retinoid metabolic pathway, a cancer or an infectious disease.
  • active ingredients include cancer antigens, pathogens of infectious diseases, antigens of the pathogens, immune cells stimulated or activated by these antigens or pathogens, and the like.
  • the cancer antigen refers to a surface antigen (so-called tumor-specific antigen) that is specifically expressed in cancer cells or tumor cells and a partial peptide of the antigen.
  • a WT1 protein that is a product of the oncogene WT1
  • a partial peptide of the protein WT1 peptides such as certain WT1 332 .
  • pathogens for infectious diseases include bacteria, fungi, viruses, protozoa, and the like.
  • antigens of pathogens include proteins expressed on the surface of bacteria, fungi, viruses and the like, glycoproteins and sugar chains, and cell walls of bacteria or fungi and constituents thereof (lipopolysaccharide, etc.).
  • immune cells stimulated or activated by antigens or pathogens include antigen-presenting cells (for example, dendritic cells, macrophages and B cells), T cells activated by the antigen-presenting cells, and the like.
  • the preventive and / or therapeutic agent, cancer immunotherapy adjuvant and immunity enhancing agent of the present invention for cancer and / or infectious diseases can be used for prevention and / or treatment of various diseases, preferably cancer or infectious diseases, particularly cancer or infection. It can be used in combination with active ingredients in immunotherapy of diseases.
  • the active ingredient include the above-described cancer antigens, pathogens of infectious diseases, antigens of the pathogens, immune cells stimulated or activated by these antigens or pathogens, and the like.
  • the subject to which the method for preventing and / or treating cancer and / or infectious diseases, the method for preventing and / or treating infectious diseases and the method for enhancing immunity may be an animal having an immune system, particularly an acquired immune system, that is, a vertebrate. If it does not specifically limit. Examples of such subjects include humans, mice, rats, dogs, cats, rabbits, horses, cows, sheep, pigs, goats, monkeys, and the like. In one preferred embodiment, such subject is a human.
  • the method for preventing and / or treating infectious disease and the method for enhancing immunity an effective amount of a retinoid metabolic pathway inhibitor administered to a subject, and a cancer antigen
  • the effective amount of the infectious disease pathogen or antigen of the pathogen or immune cells stimulated or activated by these antigens or pathogens depends on conditions such as the type of disease, the condition of the subject, the target site, etc. It can be determined as appropriate using methods well known to those skilled in the art (including various non-clinical and / or clinical trials).
  • Cancer antigens that can be used in the method for preventing and / or treating cancer and / or infectious diseases, methods for preventing and / or treating infectious diseases and methods for enhancing immunity of the present invention, pathogens of infectious diseases or antigens of the pathogens, these antigens or Examples of immune cells stimulated or activated by a pathogen are as described above.
  • Inhibitors of the retinoid metabolic pathway of the present invention include inhibitors of retinoic acid signaling systems (eg, retinoic acid receptor antagonists, dominant negative mutant proteins of retinoic acid receptors, and expression of genes encoding retinoic acid receptors).
  • RNA molecules to be suppressed eg, nucleic acid molecules that generate the RNA molecules, vectors containing the nucleic acid molecules, and the like) may be used in combination.
  • Example 1 Compound No.-1 Synthesis of RDHI-012 ( ⁇ ) Synthesis of 18 ⁇ -glycyrrhetinic acid methyl ester 2 18 ⁇ -Glycyrrhetinic acid 1 (2 g) was dissolved in methanol (20 mL), and TMS diazomethane (9.56 mL) was added dropwise under ice cooling, followed by stirring at room temperature for 20 minutes. Further, TMS diazomethane (14.56 mL) was added dropwise at room temperature, and after stirring at room temperature for 3 hours, acetic acid was added and the mixture was concentrated under reduced pressure.
  • Example 2 Synthesis of Compound No.-2 RDHI-013 ( ⁇ ) Synthesis of 18 ⁇ -glycyrrhetinic acid methyl ester 6 18 ⁇ -Glycyrrhetinic acid 5 (5 g) was dissolved in methanol (40 mL), and TMS diazomethane (10.6 mL) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. Further, TMS diazomethane (10.6 mL) was added dropwise at room temperature. After stirring at room temperature for 1 hour, acetic acid was added and the mixture was concentrated under reduced pressure.
  • Example 3 Synthesis of Compound No.-3 RDHI-014 ( ⁇ ) To Compound No.-1 (RDHI-012) ( ⁇ ) (100 mg) was added phthalic anhydride (34 mg), 1-hydroxybenzotriazole monohydrate (38 mg), and N, N-dimethylformamide (10 mL). Chilled. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (44 mg) and diisopropylethylamine (40 mg) were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine.
  • Example 4 Synthesis of Compound No.-4 RDHI-015 ( ⁇ ) N, N-dimethylformamide (10 mL) was added to Compound No.-2 (RDHI-013) ( ⁇ ) (100 mg), and phthalic anhydride (34 mg), O- (7-azabenzotriazol-1-yl)- N, N, N ′, N′-Tetramethyluronium hexafluorophosphate (87 mg) and diisopropylethylamine (53 mg) were added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine.
  • Example 5 Compound No.-5 Synthesis of RDHI-016 ( ⁇ ) To Compound No.-1 (RDHI-012) ( ⁇ ) (100 mg) was added maleic anhydride (22 mg), 1-hydroxybenzotriazole monohydrate (38 mg), and N, N-dimethylformamide (10 mL). Chilled. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (44 mg) and diisopropylethylamine (40 mg) were added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with water and saturated brine.
  • Example 7 Compound No.-7 Synthesis of RDHI-021 ( ⁇ ) Tetrahydrofuran (2 mL), triphosgene (98 mg) and activated carbon (3.2 mg) were added to compound 2 (40 mg) and stirred overnight. The reaction solution was filtered to remove activated carbon, and the filtrate was concentrated under reduced pressure. N, N-dimethylformamide (1.5 mL), L-proline methyl ester hydrochloride (16 mg) and triethylamine (25 mg) were added to the concentrate, and the mixture was stirred at room temperature for 4.5 hours. To the reaction solution was added 5% aqueous citric acid, and the mixture was extracted with ethyl acetate, and washed with water and saturated brine.
  • Example 8 Compound No. -8 Synthesis of RDHI-022 ( ⁇ ) Tetrahydrofuran (2 mL), triphosgene (98 mg) and activated carbon (3.2 mg) were added to compound 2 (40 mg) and stirred overnight. The reaction solution was filtered to remove activated carbon, and the filtrate was concentrated under reduced pressure. To the concentrate were added N, N-dimethylformamide (1.5 mL), methyl piperidine-2-carboxylate (14 mg) and triethylamine (17 ⁇ L), and the mixture was stirred at room temperature for 3.5 hours. To the reaction solution was added 5% aqueous citric acid, and the mixture was extracted with ethyl acetate, and washed with water and saturated brine.
  • Example 14 Synthesis of Compound No. -14 RDHI-028 ( ⁇ ) To Compound No.-11 RDHI-025 ( ⁇ ) (62 mg) was added methanol (3 mL) and 5M aqueous sodium hydroxide solution (146 ⁇ L), and the mixture was stirred at 40 ° C. overnight. 3M hydrochloric acid and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine.
  • Example 15 Synthesis of Compound No.-15 RDHI-031 ( ⁇ ) Synthesis of Compound 10 Toluene (2.5 mL), triethylamine (33 mg) and diphenylphosphoric acid azide (88 mg) were added to 18 ⁇ -glycyrrhetinic acid 1 (100 mg), and the mixture was stirred at 105 ° C. for 20 minutes. Methanol was added to the reaction solution and stirred overnight at room temperature, and the reaction solution was concentrated under reduced pressure. Water was added to the concentrate, and the mixture was extracted with ethyl acetate and washed with saturated brine.
  • Example 17 Synthesis of Compound No.-17 RDHI-033 ( ⁇ )
  • Compound No.-16 RDHI-032 ( ⁇ ) (100 mg) was added N, N-dimethylformamide (10 mL), acetic acid (13.2 ⁇ L), 1-hydroxybenzotriazole monohydrate (38.3 mg), and ice-cooled.
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (44.1 mg) and N, N-diisopropylethylamine (55.7 ⁇ L) were added, and the mixture was stirred at room temperature overnight. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine.
  • Example 18 Synthesis of Compound No.-18 RDHI-034 ( ⁇ )
  • Compound No.-16 RDHI-032 ( ⁇ ) (100 mg) was added with N, N-dimethylformamide (10 mL), benzoic acid (28.1 mg), 1-hydroxybenzotriazole monohydrate (38.3 mg), and iced.
  • 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (44.1 mg) and N, N-diisopropylethylamine (55.7 ⁇ L) were added, and the mixture was stirred at room temperature for 1.5 hours. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine.
  • Example 19 Compound No. -19 Synthesis of RDHI-035 ( ⁇ )
  • Compound No.-19 RDHI-035 ( ⁇ ) was synthesized from 18 ⁇ -glycyrrhetinic acid 1 by the same method as Compound No.-16 RDHI-032 ( ⁇ ) (25.1 mg).
  • Example 20 Synthesis of Compound No.-20 RDHI-039 ( ⁇ ) To compound No.-1 (RDHI-012) ( ⁇ ) (75 mg) was added dioxane (1.5 mL), water (0.75 mL) and concentrated hydrochloric acid (0.75 mL), and the mixture was sealed and stirred at 95 ° C. overnight. The reaction solution was concentrated and slurry washed with acetonitrile to obtain Compound No.-20 RDHI-039 ( ⁇ ) (46 mg).
  • Example 21 Synthesis of Compound No.-21 RDHI-040 ( ⁇ )
  • Compound No.-21 RDHI-040 ( ⁇ ) was synthesized from Compound No.-2 in the same manner as Compound No.-20 RDHI-039 ( ⁇ ) (54 mg).
  • Example 23 Synthesis of Compound No.-23 RDHI-042 ( ⁇ )
  • Compound No.-23 RDHI-042 ( ⁇ ) was synthesized from Compound No.-2 in the same manner as Compound No.-22 RDHI-041 ( ⁇ ) (44 mg).
  • Example 26 Synthesis of Compound No.-26 RDHI-045 ( ⁇ ) To Compound No.-20 (RDHI-039) ( ⁇ ) (60 mg) was added dioxane (1.0 mL), 1M aqueous sodium hydroxide solution (0.18 mL) and phthalic anhydride (19.5 mg) for 1 hour at room temperature. Stir. The reaction solution was adjusted to about pH 3 with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to obtain a crude product.
  • Example 27 Synthesis of Compound No.-27 RDHI-046 ( ⁇ ) To Compound No.-21 (RDHI-040) ( ⁇ ) (40 mg) was added dioxane (1.0 mL), 1M aqueous sodium hydroxide solution (0.239 mL) and phthalic anhydride (12.9 mg), and 3 hours at room temperature. Stir. The reaction solution was adjusted to about pH 3 with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to obtain a crude product.
  • Example 28 Inhibition of retinol dehydrogenase 10 (RDH10) enzyme activity by the compound of the present invention
  • RDH10 inhibitory activity (a) Confirmation of the presence of RDH10 in the microsomal fraction 293T cell line (1 ⁇ 10 6 cells) and Activated human CD4 + T cells (1 ⁇ 10 7 cells) were washed thoroughly with PBS, and then suspended in 600 ⁇ l of 0.25M sucrose / 0.1M Na phosphate buffer (pH 7.4). The cell suspension was homogenized and centrifuged at 10,000 g for 10 minutes at 4 ° C., and then the supernatant was centrifuged at 100,000 g for 1 hour at 4 ° C. to obtain a microsomal fraction.
  • RDH10 inhibitory activity (a) Confirmation of the presence of RDH10 in the microsomal fraction 293T cell line (1 ⁇ 10 6 cells) and Activated human CD4 + T cells (1 ⁇ 10 7 cells) were washed thoroughly with PBS, and then suspended
  • the microsomal fraction was suspended in 20 ⁇ l of 0.1 M Na phosphate buffer (pH 7.4) and used for Western blotting.
  • the RDH10 protein contained in the microsomal fraction is separated by SDS-PAGE, then transferred and blocked on the PVDF membrane, and then anti-RDH10 antibody (ab87586) as the primary antibody and anti-rabbit IgG-HRP as the secondary antibody. It reacted with the antibody and detected using Luminata Forte Western HRP Substrate (Millipore).
  • Syhergi 4 ⁇ m Hydro-RP 80A (Phenomenex) was used. The flow rate was 2.0 ml / min.
  • the enzyme activity is determined from the waveform area of the product (all-trans retinal) relative to the waveform area of the unreacted substrate (all-trans retinol), and the relative value to the enzyme activity in the control is shown in FIG. Error bars indicate SD (standard deviation). It was confirmed that the compound of the present invention inhibits RDH10 enzyme activity.
  • Compound No.-1 (RDHI-012), 2 (RDHI-013), 5 (RDHI-016), 9 (RDHI-023), 10 (RDHI-024), 14 (RDHI-028), 16 (RDHI) -032), 17 (RDHI-033), and 18 (RDHI-034) have a relatively strong RDH enzyme activity inhibitory action, particularly the compounds of Compound No. 1 (RDHI-012) and 2 (RDHI-013). It showed a strong RDH10 enzyme activity inhibitory action. Compounds RDHI-041 and 042 also showed RDH10 enzyme activity inhibitory action.
  • Example 29 Effect of the compound of the present invention in vitro CD4 + CD45RO + T cells (1 ⁇ 10 5 cells) derived from healthy subjects were treated with anti-CD3 antibody (2 ⁇ g / ml), anti-CD28 antibody (2 ⁇ g / ml), In the presence of IL-2 (20 IU / ml) and an RDH10 inhibitor (Compound No.-16 (RDHI-032), Compound No. 17 (RDHI-033) and Compound No.-18 (RDHI-034)) (each 20 ⁇ M) In culture. DMSO was used as a control for the RDH10 inhibitor.
  • effector T cells (CD62L ⁇ CD127 ⁇ T cells) were decreased.
  • the compounds RDHI-014, 016, 017, 025, 026, 035, 036, 038, 039, 040, 041, 042, 046 also showed a tendency to amplify memory cells.
  • Example 30 Effect of the compounds of the invention in vivo C57BL / 6J mice (B6 mice) are injected subcutaneously with the mouse cancer cell line EG7 (2 ⁇ 10 6 cells) expressing OVA (chicken ovalbumin). And a tumor was formed. Five days later, the tumor-formed mice were irradiated with 3 Gy, and then T cell-receptive OTCD8 + T cells (OT-1 cells) specific for OVA antigen were obtained from CD45.1-positive OT-I transgenic mice. After separation, 2 ⁇ 10 5 cells were transferred from the tail vein.
  • the RDH10 inhibitor (compound number-1 (RDHI-012) and compound number-2 (RDHI-013)) was administered at 100 ⁇ g / mouse from the tail vein three times every other day from the next day.
  • the RDH10 inhibitor was previously stocked in DMSO at 100 ⁇ g / 50 ⁇ l, and 150 ⁇ l of PBS was added thereto to give a total of 200 ⁇ l and administered to the mice.
  • FIG. 4 shows the change over time of the average value of the tumor volume after transplanting the tumor. Error bars indicate standard error. Tumor volume was determined by major axis ⁇ minor axis ⁇ height / 2. Tumor volume increased until day 12 after tumor implantation, but subsequently decreased in animals administered RDH10 inhibitors (compound number-1 (RDHI-012) and compound number-2 (RDHI-013)) On the 21st day after transplantation, the tumor volume became one-hundredth to one-hundredth. From these results, it was confirmed that RDH10 inhibitors (Compound No.-1 (RDHI-012) and Compound No.-2 (RDHI-013)) suppress tumor growth in vivo.
  • RDH10 inhibitors Compound No.-1 (RDHI-012) and Compound No.-2 (RDHI-013)
  • OT-I cells On the 20th day after tumor transplantation, the frequency of transferred OT-I cells contained in peripheral blood was analyzed by flow cytometry. Since OT-I cells were CD45.1 positive, they were clearly distinguishable from T6 cells derived from the host B6 mouse (CD45.2 positive). A typical result is shown in FIG. From these results, RDH10 inhibitors (Compound No.-1 (RDHI-012) and Compound No.-2 (RDHI-013)) induced CD45.1 + OT-1 cells (OVA-specific CD8 + cells) in vivo. Amplification was confirmed.
  • CD62L and CD127 in OT-I cells shown in FIG. 5 The expression intensity of CD62L and CD127 in OT-I cells shown in FIG. 5 was analyzed by flow cytometry. The average value and standard error of each expression intensity are shown in FIG. From these results, RDH10 inhibitors (Compound No. 1 (RDHI-012) and Compound No. -2 (RDHI-013)) were amplified in vivo in CD45.1 + OT-1 cells (OVA-specific CD8 + It was confirmed that the expression of CD62L and CD127, which are molecular markers of memory-type T cells, in cells) was enhanced.
  • a method for increasing the proportion of memory T cells in a T cell population using an inhibitor of a retinoid metabolic pathway, a cancer containing the inhibitor or a preventive and / or therapeutic agent for an infection, and a cancer containing the inhibitor And an immunopotentiator containing the inhibitor, and the like are in the fields of pharmaceuticals, for example, in the fields of development and production of drugs for the prevention and / or treatment of various diseases including cancer and infectious diseases, and methods for treating such diseases, particularly the development of immunotherapy. Is available.

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Abstract

L'invention concerne : un composé représenté par la formule (I) ; un inhibiteur de la voie métabolique du rétinoïde comprenant celui-ci ; un agent pour augmenter le rapport des lymphocytes T de la mémoire ; un agent prophylactique et/ou thérapeutique pour le cancer ou une maladie infectieuse ; un adjuvant immunothérapeutique de cancer ; un immunopotentialisateur ; et un procédé de préparation d'une population de lymphocytes T, le rapport des lymphocytes T de mémoire étant augmenté, ledit procédé comprenant l'utilisation du composé de formule (I).
PCT/JP2017/040302 2016-11-09 2017-11-08 Procédé de modification d'une population de lymphocytes t Ceased WO2018088439A1 (fr)

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DK17870242.9T DK3539974T5 (en) 2016-11-09 2017-11-08 Method for modifying t cell population
EP17870242.9A EP3539974B1 (fr) 2016-11-09 2017-11-08 Procédé de modification d'une population de lymphocytes t
JP2018550232A JP6994201B2 (ja) 2016-11-09 2017-11-08 Ｔ細胞集団の改変方法
US16/347,337 US10899790B2 (en) 2016-11-09 2017-11-08 Method for modifying T cell population
ES17870242T ES2946188T3 (es) 2016-11-09 2017-11-08 Procedimiento para modificar una población de linfocitos T

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JPWO2018088439A1 (ja) 2019-10-03
US20190284228A1 (en) 2019-09-19
EP3539974A1 (fr) 2019-09-18
EP3539974A4 (fr) 2020-05-06
US10899790B2 (en) 2021-01-26
DK3539974T5 (en) 2024-05-27

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